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Molecules 2015, 20(7), 11793-11807; doi:10.3390/molecules200711793

Inhibition of Tapeworm Thioredoxin and Glutathione Pathways by an Oxadiazole N-Oxide Leads to Reduced Mesocestoides vogae Infection Burden in Mice

1
Inmunología, Instituto de Higiene, Facultad de Química, Universidad de la República, Avda, A. Navarro 3051, Montevideo 11400, Uruguay
2
Worm Biology Laboratory, Institut Pasteur Montevideo, Mataojo 2020, Montevideo 11400, Uruguay
3
Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Química-Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay
4
Redox Biology of Trypanosomes Laboratory, Institut Pasteur Montevideo, Mataojo 2020, Montevideo 11400, Uruguay
5
Laboratorio de Experimentación Animal, Depto de Ciencias Farmacéuticas, Facultad de Química, Universidad de la República, Avda. Gral. Flores 2124, Montevideo 11800, Uruguay
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Angela Calderon
Received: 20 March 2015 / Revised: 14 June 2015 / Accepted: 18 June 2015 / Published: 26 June 2015
(This article belongs to the Special Issue Thioredoxin and Glutathione Systems)
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Abstract

Parasitic flatworms cause serious infectious diseases that affect humans and livestock in vast regions of the world, yet there are few effective drugs to treat them. Thioredoxin glutathione reductase (TGR) is an essential enzyme for redox homeostasis in flatworm parasites and a promising pharmacological target. We purified to homogeneity and characterized the TGR from the tapeworm Mesocestoides vogae (syn. M. corti). This purification revealed absence of conventional TR and GR. The glutathione reductase activity of the purified TGR exhibits a hysteretic behavior typical of flatworm TGRs. Consistently, M. vogae genome analysis revealed the presence of a selenocysteine-containing TGR and absence of conventional TR and GR. M. vogae thioredoxin and glutathione reductase activities were inhibited by 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole N2-oxide (VL16E), an oxadiazole N-oxide previously identified as an inhibitor of fluke and tapeworm TGRs. Finally, we show that mice experimentally infected with M. vogae tetrathyridia and treated with either praziquantel, the reference drug for flatworm infections, or VL16E exhibited a 28% reduction of intraperitoneal larvae numbers compared to vehicle treated mice. Our results show that oxadiazole N-oxide is a promising chemotype in vivo and highlights the convenience of M. vogae as a model for rapid assessment of tapeworm infections in vivo. View Full-Text
Keywords: thioredoxin reductase; glutathione reductase; thioredoxin glutathione reductase; oxadiazole N-oxide; Mesocestoides; tapeworms thioredoxin reductase; glutathione reductase; thioredoxin glutathione reductase; oxadiazole N-oxide; Mesocestoides; tapeworms
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Pasquet, V.; Bisio, H.; López, G.V.; Romanelli-Cedrez, L.; Bonilla, M.; Saldaña, J.; Salinas, G. Inhibition of Tapeworm Thioredoxin and Glutathione Pathways by an Oxadiazole N-Oxide Leads to Reduced Mesocestoides vogae Infection Burden in Mice. Molecules 2015, 20, 11793-11807.

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